Medical use of pharmaceutical combination or composition

ABSTRACT

The present invention relates to a certain DPP-4 inhibitor for use in combination with metformin in CKD patients.

FIELD OF THE INVENTION

The present invention relates to a certain DPP-4 inhibitor (preferablylinagliptin) for use in combination with metformin (particularly in theform of metformin hydrochloride) in CKD (chronic kidney disease)patients, particularly in patients having CKD up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45, or even down to 30, such as in patients with CKD ofmoderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59or of moderate-to-severe stage such as having eGFR levels 30-44 (CKDstage 3b), optionally in combination with one or more other activesubstances.

BACKGROUND OF THE INVENTION

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion with theconsequence not meeting the required demands to maintain plasma glucoselevels in the normal range. This leads to chronic hyperglycaemia and itsassociated micro- and macrovascular complications or chronic damages,such as e.g. diabetic nephropathy, retinopathy or neuropathy, ormacrovascular (e.g. cardio- or cerebro-vascular) complications, and/orcognitive function impairment. The vascular disease component plays asignificant role, but is not the only factor in the spectrum of diabetesassociated disorders. The high frequency of complications leads to asignificant reduction of life expectancy. Diabetes is currently the mostfrequent cause of adult-onset loss of vision, renal failure, andamputation in the Industrialized World because of diabetes inducedcomplications and is associated with a two to five fold increase incardiovascular disease risk. The elevated risk for macrovascular diseaseis primarily related to increased risk for athero-thrombosis that leadsto increased morbidity and premature mortality from cardiovascular (CV)disease and an important predictor for CV diseases is renal impairment,nephropathy and/or chronic kidney disease (CKD) which often co-exists.

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required. But, because type 2 diabetes is a progressive disease,even patients with good initial responses to conventional combinationtherapy will eventually require an increase of the dosage or furthertreatment with an additional oral or non-oral antidiabetic drug (oftenfinally with insulin therapy) because the blood glucose level is verydifficult to maintain stable for a long period of time. Althoughexisting combination therapy has the potential to enhance glycemiccontrol, it is not without limitations (especially with regard to longterm efficacy). Further, traditional therapies may show an increasedrisk for side effects, such as hypoglycemia or weight gain, which maycompromise their efficacy and acceptability.

Thus, for many patients, these existing drug therapies result inprogressive deterioration in metabolic control despite treatment and donot sufficiently control metabolic status especially over long-term andthus fail to achieve and to maintain glycemic control in advanced,progressed or late stage type 2 diabetes, including diabetes withinadequate glycemic control despite conventional oral and/or non-oralantidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with diabetes remaininadequately treated, partly because of limitations in long termefficacy, safety/tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

In addition, obesity, overweight or weight gain (e.g. as side or adverseeffect of some conventional antidiabetic medications) furthercomplicates the treatment of diabetes and its microvascular ormacrovascular, and/or cognitive, complications.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and macrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cerebro- orcardiovascular complications such as e.g. myocardial infarction, strokeor vascular mortality or morbidity) in patients with diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first-, second- or third-line, and/or mono- or (initial or add-on)combination therapy) may include, without being restricted thereto,metformin, sulphonylureas, thiazolidinediones, glinides andα-glucosidase inhibitors.

Non-oral (typically injected) antidiabetic drugs conventionally used intherapy (such as e.g. first-, second- or third-line, and/or mono- or(initial or add-on) combination therapy) may include, without beingrestricted thereto, GLP-1 or GLP-1 analogues, and insulin or insulinanalogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting).

In addition to morbidity associated with each of these side effects,they could also have adverse cardiovascular implications. For example,hypoglycaemia and weight gain are postulated as contributors to adverseCV mortality outcomes.

Hypoglycemic episodes have also been identified detrimental to cognitiveskills and are associated with a greater risk of cognitive impairment ordementia. The risk of hypoglycemia is further increased in the elderlywith comorbidities and multiple medication use.

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies.

In particular, a certain amount of people with type 2 diabetes mellitushave chronic kidney disease (CKD). For these individuals, the currentstandard of care is intensive glycemic control and treatment withangiotensin-converting enzyme (ACE) inhibitors or angiotensin IIreceptor blockers (ARBs).

Despite such treatment, type 2 diabetes patients with chronic kidneydisease (particularly having residual albuminuria) still havesubstantial risk for cardio-renal morbidity and mortality, an unmet needthat is driving a search for novel therapies for diabetic kidneydisease.

Accordingly, it remains a need in the art to provide efficacious, safeand tolerable antidiabetic therapies both for diabetic patients such aswho have not previously been treated with an antidiabetic drug(drug-naïve patients) and, particularly, for patients with advanced orlate stage type 2 diabetes mellitus, including patients with inadequateglycemic control on conventional oral and/or non-oral antidiabeticdrugs, such as e.g. metformin, sulphonylureas, thiazolidinediones,glinides and/or α-glucosidase inhibitors, and/or GLP-1 or GLP-1analogues, and/or insulin or insulin analogues; particularly in patientswith (chronic) renal disease, renal dysfunction or renal impairment,including in patients having chronic kidney disease (CKD) such as e.g.up to stage 3 and/or having estimated glomerular filtration rate (eGFR;mL/minute/1.73 m²) levels down to 45 or even down to 30, such as inpatients with (chronic) renal impairment of moderate stage (CKD stage 3,eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)having eGFR levels 45-59, or even of moderate-to-severe stage havingeGFR levels 30-44 (CKD stage 3b).

Particularly, it is a need for therapies for diabetic patients withmoderate-to-severe microvascular burden, such as advanced kidneydisease.

Further, within the therapy of type 2 diabetes, it is a need fortreating the condition effectively, avoiding the (micro- and/ormacrovascular) complications inherent to the condition, and delaying ormodifying disease progression, e.g. in order to achieve a long-lastingtherapeutic benefit.

Furthermore, it remains a need that antidiabetic treatments not onlyprevent and/or treat the long-term complications often found in advancedstages of diabetes disease, but also are a therapeutic option in thosediabetes patients who have developed or are at-risk of developing suchcomplications (e.g. chronic kidney disease/diabetic nephropathy, renalimpairment and/or albuminuria).

There is a need that antidiabetic treatments prevent and/or treatpreferably both microvascular (renal) complications and macrovascular(CV) complications together, preferably within one therapy.

There is also a need to provide a therapeutic option in those diabetespatients who have developed or are at-risk of developing bothmicrovascular (renal) complications and macrovascular (CV)complications.

Also, there is a need that antidiabetic treatments prevent and/or treataccelerated cognitive decline (which may be associated with micro-and/or macrovascular complications), preferably together with bothmicrovascular (renal) complications and macrovascular (CV)complications, preferably within one therapy.

Moreover, it remains a need to provide prevention or reduction of riskfor adverse effects associated with conventional antidiabetic therapies.

SUMMARY OF THE INVENTION

The present invention relates to use of a certain DPP-4 inhibitor(preferably linagliptin) in combination with metformin (particularly inthe form of metformin hydrochloride) in CKD (chronic kidney disease)patients, particularly in patients having CKD up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45, or even down to 30, such as in patients with CKD ofmoderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59or of moderate-to-severe stage such as having eGFR levels 30-44 (CKDstage 3b), optionally in combination with one or more other activesubstances.

The present invention relates to certain medical uses of a combinationor a pharmaceutical composition comprising a certain DPP-4 inhibitor(preferably linagliptin) and metformin (particularly in the form ofmetformin hydrochloride), such as e.g. for treating and/or preventingmetabolic diseases, especially type 2 diabetes mellitus and/orconditions related thereto (e.g. diabetic complications), including inpatients with (chronic) renal disease, renal dysfunction or renalimpairment, particularly in patients having chronic kidney disease (CKD)such as e.g. up to stage 3 and/or having estimated glomerular filtrationrate (eGFR; mL/minute/1.73 m²) levels down to 45, or even down to 30,such as in patients with (chronic) renal impairment of moderate stage(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage (CKDstage 3a) such as having eGFR levels 45-59 or of moderate-to-severestage such as having eGFR levels 30-44 (CKD stage 3b); optionally incombination with one or more other active substances.

The present invention further relates to the medical use of acombination or a pharmaceutical composition comprising a certain DPP-4inhibitor (preferably linagliptin) and metformin (particularly in theform of metformin hydrochloride), for treating and/or preventing chronickidney disease (CKD) such as e.g. up to stage 3 and/or having estimatedglomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45,or even down to 30, such as of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59 or of moderate-to-severe stage such as having eGFRlevels 30-44 (CKD stage 3b); optionally in combination with one or moreother active substances (such as e.g. antidiabetic and/or anangiotensin-converting enzyme (ACE) inhibitor or an angiotensin IIreceptor blocker (ARB)).

The present invention yet further relates to a certain DPP-4 inhibitor(preferably linagliptin) in combination with metformin (particularly inthe form of metformin hydrochloride) (and optionally in combination withone or more other active agents) for use in therapy, prophylaxis,treatment or prevention of diabetic (preferably type 2 diabetes)patients (preferably for use in cardio- and/or renoprotective therapypreferably of type 2 diabetes in human patients),

including in patients (preferably type 2 diabetes patients) with(chronic) renal disease, renal dysfunction or renal impairment,particularly in patients having chronic kidney disease (CKD) such ase.g. up to stage 3 and/or having estimated glomerular filtration rate(eGFR; mL/minute/1.73 m²) levels down to 45, or even down to 30, such asin patients with (chronic) renal impairment of moderate stage (CKD stage3, eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)such as having eGFR levels 45-59 or of moderate-to-severe stage such ashaving eGFR levels 30-44 (CKD stage 3b); optionally in combination withone or more other active substances.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin) for use in combination with metformin(particularly in the form of metformin hydrochloride), such as e.g. suchas e.g. for treating type 2 diabetes and treating, decreasing, delayingthe onset and/or delaying the progression of diabetic nephropathy,chronic kidney disease, albuminuria (e.g. micro- or macro-albuminuria),renal impairment, retinopathy, neuropathy, learning or memory orcognitive impairment or decline, neurodegenerative or cognitivedisorders such as dementia, and/or macrovascular complications such ascardio- or cerebrovascular events such as stroke or myocardialinfarction, in patients with type 2 diabetes and micro- ormacroalbuminuria, with or without renal function impairment, such aspatients with CKD (chronic kidney disease), particularly patients havingCKD up to stage 3 and/or having estimated glomerular filtration rate(eGFR; mL/minute/1.73 m²) levels down to 45, or even down to 30, such aspatients with CKD of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59 or of moderate-to-severe stage such as having eGFRlevels 30-44 (CKD stage 3b), optionally in combination with one or moreother active substances.

The present invention relates to a DPP-4 inhibitor (preferablylinagliptin) in combination with metformin (particularly in the form ofmetformin hydrochloride), for use in treating and/or preventing(including slowing the progression or delaying the onset) of metabolicdiseases, particularly diabetes (especially type 2 diabetes mellitus)and/or conditions related thereto (e.g. diabetic complications,particularly diabetic chronic kidney disease); including in patientswith (chronic) renal disease, renal dysfunction or renal impairment(impairment of renal function), particularly in patients having chronickidney disease (CKD) such as e.g. up to stage 3 and/or having estimatedglomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45or even down to 30, such as in patients with (chronic) renal impairmentof moderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59,or even of moderate-to-severe stage such as having eGFR levels 30-44(CKD stage 3b), with or without residual albuminuria (micro- ormacroalbuminuria), optionally in combination with one or more otheractive substances.

Accordingly, the present invention further relates to a DPP-4 inhibitor(preferably linagliptin, preferably in a daily dose of 5 mg,administered 5 mg once daily or 2.5 mg twice daily) for use incombination with metformin (particularly in the form of metforminhydrochloride) in treating and/or preventing (including slowing theprogression or delaying the onset) of metabolic diseases, particularlydiabetes (especially type 2 diabetes mellitus) and/or conditions relatedthereto (e.g. diabetic complications, such as one or more selected fromdiabetic chronic kidney disease, nephropathy, micro- ormacroalbuminuria, renal impairment, retinopathy, neuropathy, learning ormemory or cognitive impairment or decline, neurodegenerative orcognitive disorders such as dementia, and/or macrovascular complicationssuch as cardio- or cerebrovascular events such as stroke and/ormyocardial infarction); including in patients with (chronic) renaldisease, renal dysfunction or renal impairment (impairment of renalfunction), particularly in patients having chronic kidney disease (CKD)such as e.g. up to stage 3 and/or having estimated glomerular filtrationrate (eGFR; mL/minute/1.73 m²) levels down to 45 or even down to 30,such as in patients with (chronic) renal impairment of moderate stage(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage (CKDstage 3a) such as having eGFR levels 45-59, or even ofmoderate-to-severe stage such as having eGFR levels 30-44 (CKD stage3b), with or without residual albuminuria (micro- or macroalbuminuria),optionally in combination with one or more other active substances (suchas selected from other antidiabetics and/or ACE inhibitors or ARBs),particularly wherein the maximum daily dose of metformin (particularlyin the form of metformin hydrochloride) administered to patients ofmild-to-moderate stage (CKD stage 3a, such as having eGFR levels 45-59)is 2000 mg, and/or particularly wherein the maximum daily dose ofmetformin (particularly in the form of metformin hydrochloride)administered to patients of moderate-to-severe stage (CKD stage 3b, suchas having eGFR levels 30-44) is 1000 mg.

Also, the present invention relates to a pharmaceutical combination orcomposition comprising a DPP-4 inhibitor (preferably linagliptin),metformin (particularly in the form of metformin hydrochloride) andoptionally one or more pharmaceutically acceptable auxiliaries, for usein treating and/or preventing (including slowing the progression ordelaying the onset) of metabolic diseases, particularly diabetes(especially type 2 diabetes mellitus) and/or conditions related thereto(e.g. diabetic complications, particularly diabetic chronic kidneydisease), including in patients with (chronic) renal disease, renaldysfunction or renal impairment (impairment of renal function),particularly in patients having chronic kidney disease (CKD) such ase.g. up to stage 3 and/or having estimated glomerular filtration rate(eGFR; mL/minute/1.73 m²) levels down to 45 or even down to 30, such asin patients with (chronic) renal impairment of moderate stage (CKD stage3, eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)such as having eGFR levels 45-59, or of moderate-to-severe stage such ashaving eGFR levels 30-44 (CKD stage 3b), with or without residualalbuminuria (micro- or macroalbuminuria); optionally in combination withone or more other active substances.

Also, the present invention relates to a combination therapy comprisingusing a DPP-4 inhibitor (preferably linagliptin) and metformin(particularly in the form of metformin hydrochloride) for treatingand/or preventing (including slowing the progression or delaying theonset) of metabolic diseases, particularly diabetes (especially type 2diabetes mellitus) and/or conditions related thereto (e.g. diabeticcomplications, particularly diabetic chronic kidney disease), includingin patients with (chronic) renal disease, renal dysfunction or renalimpairment (impairment of renal function), particularly in patientshaving chronic kidney disease (CKD) such as e.g. up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45 or even down to 30, such as in patients with (chronic)renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59, or of moderate-to-severe stage such as having eGFRlevels 30-44 (CKD stage 3b), with or without residual albuminuria(micro- or macroalbuminuria); optionally in combination with one or moreother active substances.

The present invention further relates to a certain DPP-4 inhibitor(preferably linagliptin) in combination with metformin (particularly inthe form of metformin hydrochloride), and optionally in combination withone or more other active agents, for use in therapy or treatment ofdiabetes (preferably type 2 diabetes) in (human) patients in needthereof, preferably for use in cardio- and/or renoprotective therapypreferably of type 2 diabetes in human patients, such as e.g. includingtreating type 2 diabetes and/or preventing diabetic complications

such as decreasing, protecting against, delaying the onset, slowingprogression and/or reducing the risk of (cardio)vascular and/or renalmorbidity and/or mortality, such as e.g.

-   -   i) treating, preventing or delaying the progression of chronic        kidney disease (diabetic nephropathy); and/or    -   ii) treating, decreasing, preventing, protecting against,        delaying the progression, delaying the occurrence and/or        reducing the risk of albuminuria (e.g. micro- or        macro-albuminuria) and/or renal impairment; and/or    -   iii) preventing, protecting against, reducing the risk of and/or        delaying the occurrence of a cardio- or cerebrovascular disease,        complication or event selected from: cardiovascular (CV) death        (including fatal stroke, fatal myocardial infarction and sudden        death), non-fatal stroke, non-fatal myocardial infarction (MI)        (silent MI may be excluded) and, optionally, hospitalization for        unstable angina pectoris; and/or    -   iv) preventing, protecting against, reducing the risk of,        delaying the progression and/or delaying the occurrence of a        renal microvascular disease, complication or event selected        from: renal death, end-stage renal disease and loss in estimated        glomerular filtration rate (e.g. eGFR ≥50% from baseline);        and/or    -   v) decreasing, preventing, protecting against, delaying (e.g.        occurrence or progression) and/or reducing the risk of        (accelerated) cognitive decline or cognitive impairment or        dementia;    -   including in patients (preferably type 2 diabetes patients) with        (chronic) renal disease, renal dysfunction or renal impairment,        particularly in patients having chronic kidney disease (CKD)        such as e.g. up to stage 3 and/or having estimated glomerular        filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45, or        even down to 30, such as in patients with (chronic) renal        impairment of moderate stage (CKD stage 3, eGFR 30-60),        particularly of mild-to-moderate stage (CKD stage 3a) such as        having eGFR levels 45-59 or of moderate-to-severe stage such as        having eGFR levels 30-44 (CKD stage 3b); optionally in        combination with one or more other active substances; wherein        such patients may be with or at-risk of further (major) (micro-        and/or macro-)vascular diseases, complications or events, e.g.        such patients may be at high vascular risk.

Other aspects of the present invention become apparent to the skilledperson from the foregoing and following remarks (including the examplesand claims).

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of the present invention it has now been found thatcertain DPP-4 inhibitors as defined herein as well as combinations orpharmaceutical compositions of these DPP-4 inhibitors with metformin(particularly in the form of metformin hydrochloride) as well as theiruse have particularly useful properties or effects, which make themsuitable for the purpose of this invention and/or for fulfilling one ormore of the needs mentioned herein.

For example, combinations or pharmaceutical compositions of these DPP-4inhibitors with metformin (particularly in the form of metforminhydrochloride) are useful for improving glycemic control and/or fortreating and/or preventing (including slowing the progression ordelaying the onset) of metabolic diseases, particularly diabetes(especially type 2 diabetes mellitus) and/or conditions related thereto(e.g. diabetic complications, particularly diabetic chronic kidneydisease, or diabetic nephropathy, micro-or macroalbuminuria and/or renalimpairment), such as in drug naïve type 2 diabetes patients and/or inpatients with advanced or late stage type 2 diabetes, including patientswith insufficient glycemic control despite a therapy with an oral and/ora non-oral antidiabetic or antihyperglycemic drug and/or with indicationon insulin; including in patients with (chronic) renal disease, renaldysfunction or renal impairment, particularly in patients having chronickidney disease (CKD) such as e.g. up to stage 3 and/or having estimatedglomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45or even down to 30, such as in patients with (chronic) renal impairmentof moderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59,or even of moderate-to-severe stage such as having eGFR levels 30-44(CKD stage 3b), with or without residual albuminuria, especiallyincluding in patients with (chronic) renal impairment ofmild-to-moderate stage (CKD stage 3a) such as having estimatedglomerular filtration rate [eGFR] 45-59 mL/minute/1.73 m² or creatinineclearance [CrCl] 45-59 mL/min, optionally in combination with one ormore other active substances.

For example, patients having chronic kidney disease (CKD) such as e.g.up to stage 3 and/or having estimated glomerular filtration rate (eGFR;mL/minute/1.73 m²) levels down to 45 or even down to 30 are amenable tothe combination therapy according to the present invention comprisingusing linagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. up to maximum total daily dose of 1000 mg metforminhydrochloride (such as e.g. for CKD 3a patients) or 2000 mg metforminhydrochloride (such as e.g. for CKD 3b patients)), preferably using atablet containing 2.5 mg linagliptin and 500 mg, 850 mg or 1000 mgmetformin hydrochloride (in immediate release form) each administeredtwice daily, or using a tablet containing 5 mg linagliptin and 1000 mgmetformin hydrochloride (in extended release form) administered oncedaily, or using a tablet containing 2.5 mg linagliptin and 750 mg or1000 mg metformin hydrochloride (in extended release form) eachadministered as two tablets once daily.

In an embodiment, the maximum daily dose of metformin (particularly inthe form of metformin hydrochloride) administered to patients ofmild-to-moderate stage (CKD stage 3a, such as having eGFR levels 45-59)may be 2000 mg, which may be given as two divided doses, such as e.g.1000 mg twice daily; (the starting dose may be at most half of themaximum dose).

In an embodiment, the maximum daily dose of metformin (particularly inthe form of metformin hydrochloride) administered to patients ofmoderate-to-severe stage (CKD stage 3b, such as having eGFR levels30-44) may be 1000 mg, which may be given as two divided doses, such ase.g. 500 mg twice daily; (the starting dose may be at most half of themaximum dose).

For patients with severe or very severe stage of renal impairment (CKDstage 4, such as having eGFR levels <30; or CKD stage 5, such as havingeGFR levels <15, end-stage renal disease), metformin is contraindicated.

The combination therapy according to the present invention usinglinagliptin (in a total daily dose of 5 mg) in combination withmetformin is also useful for patients in need of >1000 mg metformindaily (e.g. 850 mg or 1000 mg metformin hydrochloride BID) forsufficient glycemic control and having chronic kidney disease (CKD),such as e.g. up to stage 3 and/or having estimated glomerular filtrationrate (eGFR; mL/minute/1.73 m²) levels down to 45 (or, in certaininstances, even down to 30); preferably by using a tablet containing 2.5mg linagliptin and 850 mg or 1000 mg metformin hydrochloride (inimmediate release form) each administered twice daily, or using a tabletcontaining 2.5 mg linagliptin and 750 mg or 1000 mg metforminhydrochloride (in extended release form) each administered as twotablets once daily.

For further example, patients in need of >1000 mg metformin daily (e.g.1000 mg metformin hydrochloride BID) for sufficient glycemic control butwith dose limitation for metformin due to renal impairment (e.g. maximumtotal daily dose of 1000 mg metformin hydrochloride), such as havingmoderate renal impairment, e.g., in certain instances, patients with(chronic) renal impairment of mild-to-moderate stage (CKD stage 3a) suchas having eGFR levels 45-59 mL/minute/1.73 m², or especially ofmoderate-to-severe stage (CKD stage 3b) such as having eGFR levels 30-44mL/minute/1.73 m², benefit from the combination therapy according to thepresent invention comprising using linagliptin (in a total daily dose of5 mg) in combination with metformin (e.g. up to maximum total daily doseof 1000 mg metformin hydrochloride), preferably using a tabletcontaining 2.5 mg linagliptin and 500 mg metformin hydrochloride,administered twice daily.

Accordingly, patients with dose limitation for metformin due to renalimpairment (e.g. maximum total daily dose of 2000 mg metforminhydrochloride), e.g. with (chronic) renal impairment of mild-to-moderatestage (CKD stage 3a) such as having eGFR levels 45-59 mL/minute/1.73 m²,benefit from the combination therapy according to the present inventioncomprising using linagliptin (in a total daily dose of 5 mg) incombination with metformin (e.g. up to maximum total daily dose of 2000mg metformin hydrochloride), preferably using a tablet containing 2.5 mglinagliptin and 1000 mg metformin hydrochloride, administered twicedaily.

Accordingly, patients with dose limitation for metformin due to renalimpairment (e.g. maximum total daily dose of 1000 mg metforminhydrochloride), e.g. with (chronic) renal impairment ofmoderate-to-severe stage (CKD stage 3b) such as having eGFR levels 30-44mL/minute/1.73 m², benefit from the combination therapy according to thepresent invention comprising using linagliptin (in a total daily dose of5 mg) in combination with metformin (e.g. up to maximum total daily doseof 1000 mg metformin hydrochloride), preferably using a tabletcontaining 2.5 mg linagliptin and 500 mg metformin hydrochloride,administered twice daily.

In an embodiment, patients on linagliptin (in a total daily dose of 5mg) in combination with metformin (up to maximum total daily dose of2000 mg metformin hydrochloride), using a tablet containing 2.5 mglinagliptin and 850 mg, administered twice daily, or a tablet containing2.5 mg linagliptin and 1000 mg metformin hydrochloride, administeredtwice daily, can maintain these treatments until they reach an eGFR of45 mL/min/1.73 m² (this would not be the case for patients using anothermajor DPP-4 inhibitor (gliptin) other than linagliptin, requiring doseadjustment of the DPP-4 inhibitor component leading to change in thetreatment scheme, except for linagliptin).

In a further embodiment, patients with an eGFR between 45 and 59mL/min/1.73 m² (CKD stage 3a) already on the maximum dose of metformin(e.g. maximum total daily dose of 2000 mg metformin hydrochloride) canuse linagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. maximum total daily dose of 2000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 1000 mg metformin hydrochloride, administered twice daily, whenadditional therapy is deemed necessary.

In a further embodiment, patients on linagliptin (in a total daily doseof 5 mg) in combination with metformin (e.g. up to maximum total dailydose of 1000 mg metformin hydrochloride), using a tablet containing 2.5mg linagliptin and 500 mg, administered twice daily, can maintain thesetreatments until they reach an eGFR of 30 mL/min/1.73 m² (this would notbe the case for patients using another major DPP-4 inhibitor (gliptin)other than linagliptin, requiring dose adjustment of the DPP-4 inhibitorcomponent leading to change in the treatment scheme, except forlinagliptin).

In a further embodiment, patients with an eGFR between 30 and 44mL/min/1.73 m² (CKD stage 3b) already on the maximum dose of metformin(e.g. maximum total daily dose of 1000 mg metformin hydrochloride) canuse linagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. maximum total daily dose of 1000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 500 mg metformin hydrochloride, administered twice daily, whenadditional therapy is deemed necessary.

In a yet further embodiment, patients with an eGFR between 45 and 59mL/min/1.73 m² (CKD stage 3a) who are not receiving metformin canup-titrate to the maximum dose of metformin (e.g. up to maximum totaldaily dose of 2000 mg metformin hydrochloride) and can then start to uselinagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. up to maximum total daily dose of 2000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 850 mg or 1000 mg metformin hydrochloride, administered twice daily.

In a yet further embodiment, patients with an eGFR between 30 and 44mL/min/1.73 m² (CKD stage 3b) who are not receiving metformin canup-titrate to the maximum dose of metformin (e.g. up to maximum totaldaily dose of 1000 mg metformin hydrochloride) and can then start to uselinagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. up to maximum total daily dose of 1000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 500 mg metformin hydrochloride, administered twice daily.

In a still yet further embodiment, patients with an eGFR between 45 and59 mL/min/1.73 m² (CKD stage 3a) who are not receiving metformin can uselinagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. up to maximum total daily dose of 2000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 850 mg or 1000 mg metformin hydrochloride, administered twice daily,to start treatment.

In a still yet further embodiment, patients with an eGFR between 30 and44 mL/min/1.73 m² (CKD stage 3b) who are not receiving metformin can uselinagliptin (in a total daily dose of 5 mg) in combination withmetformin (e.g. up to maximum total daily dose of 1000 mg metforminhydrochloride), preferably using a tablet containing 2.5 mg linagliptinand 500 mg metformin hydrochloride, administered twice daily, to starttreatment.

It has been found that 2.5 mg linagliptin/500 mg metformin hydrochlorideBID combination therapy is at least as effective as 1000 mg metforminBID monotherapy, thereby offering an alternative for patients intolerantto such high dose of metformin or with dose limit for metformin due torenal impairment.

The combination therapy according to this invention using a DPP-4inhibitor (particularly linagliptin) and metformin (e.g. 2.5 mglinagliptin/500 mg metformin hydrochloride BID) is more effective forpatients with (chronic) renal impairment, such as of mild-to-moderatestage (CKD stage 3a) or even of moderate-to-severe stage (CKD stage 3b),than metformin alone.

Accordingly, a particular embodiment of the combination therapyaccording to the present invention for patients with (chronic) renalimpairment (CKD) relates to 2.5 mg linagliptin/500 mg metforminhydrochloride BID.

A more particular embodiment of the combination therapy according to thepresent invention relates to 2.5 mg linagliptin/500 mg metforminhydrochloride administered twice daily to patients with (chronic) renalimpairment of moderate-to-severe stage such as having eGFR levels 30-44(CKD stage 3b).

Further, the combination therapy according to this invention using aDPP-4 inhibitor (particularly linagliptin) and metformin (optionally incombination with one or more further active agents) has beneficialpotential on cardio-renal morbidity and/or mortality (cardio-and/orrenoprotection) in diabetic kidney disease patients as described herein(especially in type 2 diabetes patients with advanced CKD and/or overlong-term treatment):

For example, the combination therapy according to the present inventionusing a DPP-4 inhibitor (particularly linagliptin) and metformin(optionally in combination with one or more further active agents)

-   -   i) prevents, protects against, reduces the risk of and/or delays        the occurrence of a cardio- or cerebrovascular disease,        complication or event selected from: cardiovascular (CV) death        (including fatal stroke, fatal myocardial infarction and sudden        death), non-fatal stroke, non-fatal myocardial infarction (MI)        (silent MI may be excluded) and, optionally, hospitalisation for        unstable angina pectoris; and/or    -   ii) prevents, protects against, reduces the risk of, delays the        progression and/or delays the occurrence of a renal        microvascular disease, complication or event selected from:        renal death, end-stage renal disease and loss in estimated        glomerular filtration rate (e.g. eGFR ≥50% from baseline).

For further example, the combination therapy according to the presentinvention using a DPP-4 inhibitor (particularly linagliptin) andmetformin (optionally in combination with one or more further activeagents)

-   -   i) prevents, protects against, reduces the risk of, delays the        progression and/or delays the occurrence of a renal        microvascular disease, complication or event selected from:        renal death, end-stage renal disease and loss in estimated        glomerular filtration rate (e.g. eGFR ≥50% from baseline).

For yet further example, the combination therapy according to thepresent invention using a DPP-4 inhibitor (particularly linagliptin) andmetformin (optionally in combination with one or more further activeagents)

-   -   i) decreases, prevents, protects against, delays (e.g.        occurrence or progression) and/or reduces the risk of        (accelerated) cognitive decline or cognitive impairment or        dementia.

For yet further example, the combination therapy according to thepresent invention using a DPP-4 inhibitor (particularly linagliptin) andmetformin (optionally in combination with one or more further activeagents)

-   -   i) treats, decreases, prevents, protects against, delays (e.g.        occurrence or progression) and/or reduces the risk of diabetic        nephropathy.

For yet further example, the combination therapy according to thepresent invention using a DPP-4 inhibitor (particularly linagliptin) andmetformin (optionally in combination with one or more further activeagents)

-   -   i) treats, decreases, prevents, protects against, delays (e.g.        occurrence or progression) and/or reduces the risk of        albuminuria (e.g. micro- or macroalbuminuria).

For yet further example, the combination therapy according to thepresent invention using a DPP-4 inhibitor (particularly linagliptin) andmetformin (optionally in combination with one or more further activeagents)

-   -   i) treats, decreases, prevents, protects against, delays (e.g.        occurrence or progression) and/or reduces the risk of renal        impairment.

Accordingly, a combination therapy according to the present inventionusing a DPP-4 inhibitor (particularly linagliptin) and metformin isparticularly useful for treating and/or preventing (including delayingthe onset or slowing the progression) of metabolic diseases,particularly diabetes (especially type 2 diabetes mellitus) and/orconditions related thereto (e.g. diabetic complications, particularlydiabetic chronic kidney disease, or diabetic nephropathy, micro-ormacroalbuminuria and/or renal impairment), in patients with (chronic)renal disease, renal dysfunction or renal impairment, particularly inpatients having chronic kidney disease (CKD) such as e.g. up to stage 3and/or having estimated glomerular filtration rate (eGFR; mL/minute/1.73m²) levels down to 45 or even down to 30, such as in patients with(chronic) renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59, or even of moderate-to-severe stage such as havingeGFR levels 30-44 (CKD stage 3b), with or without albuminuria,especially including in patients with (chronic) renal impairment ofmild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59;

-   -   optionally in combination with one or more other active        substances, such as e.g. any of those mentioned herein,    -   such as e.g. optionally in combination with one or more other        antidiabetics such as selected from a sulphonylurea, a        thiazolidinedione (e.g. pioglitazone), a glinide, an        alpha-glucosidase blocker, GLP-1 or a GLP-1 analogue, and        insulin or an insulin analogue, and/or an angiotensin converting        enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

Further, the combination therapy according to the present inventionusing a DPP-4 inhibitor (particularly linagliptin) and metformin isparticularly useful for treating and/or preventing (including delayingthe onset or slowing the progression) of renal microvascular disease,such as selected from (diabetic) chronic kidney disease (CKD), diabeticnephropathy, albuminuria (e.g. micro- or macro-albuminuria), renalimpairment, renal death, end-stage renal disease and/or loss inestimated glomerular filtration rate (e.g. eGFR>=50% from baseline), inpatients (particularly in type 2 diabetes patients) with (chronic) renaldisease, renal dysfunction or renal impairment, particularly in patientshaving chronic kidney disease

(CKD, particularly advanced CKD), such as e.g. up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45 or even down to 30, such as in patients with (chronic)renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59, or even of moderate-to-severe stage such as havingeGFR levels 30-44 (CKD stage 3b), with or without albuminuria,especially including in patients with (chronic) renal impairment ofmild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59;optionally in combination with one or more other active substances, suchas e.g. any of those mentioned herein,

such as e.g. optionally in combination with one or more otherantidiabetics such as selected from a sulphonylurea, a thiazolidinedione(e.g. pioglitazone), a glinide, an alpha-glucosidase blocker, GLP-1 or aGLP-1 analogue, and insulin or an insulin analogue, and/or anangiotensin converting enzyme (ACE) inhibitor or an angiotensin receptorblocker (ARB); particularly over long-term treatment.

An embodiment of patients with (chronic) renal impairment (CKD) asdescribed herein relates to type 2 diabetes patients having impairedrenal function such as indicated herein with micro- or macroalbuminuria(e.g. urine albumin creatinine ratio (UACR) 30-3000 mg/g creatinine).

Another embodiment of patients with (chronic) renal impairment (CKD) asdescribed herein relates to type 2 diabetes patients having impairedrenal function such as indicated herein without micro- ormacroalbuminuria (e.g. urine albumin creatinine ratio (UACR) 30-3000mg/g creatinine).

A sub-embodiment of patients with (chronic) renal impairment (CKD) asdescribed herein relates to type 2 diabetes patients having impairedrenal function of moderate-to-severe stage (CKD 3b) with any albuminuria(e.g. urine albumin creatinine ratio (UACR) >=30 mg/g creatinine).

Another sub-embodiment of patients with (chronic) renal impairment (CKD)as described herein relates to type 2 diabetes patients having impairedrenal function of up to mild-to-moderate stage (CKD 3a) withmacro-albuminuria (e.g. urine albumin creatinine ratio (UACR) >200 mg/gcreatinine).

A further embodiment of patients with (chronic) renal impairment (CKD)as described herein relates to type 2 diabetes patients at early stagesof prevalent renal microvascular complications, such as e.g. havingmicroalbuminuria (e.g. 30-200 or 30-300 mg/g creatinine) and/or earlyimpaired renal function (eGFR, and/or early CKD stage).

Another further embodiment of patients with (chronic) renal impairment(CKD) as described herein relates to type 2 diabetes patients atadvanced stages of prevalent renal microvascular complications, such ase.g. having macroalbuminuria (e.g. >200 or >300 mg/g creatinine) and/oradvanced impaired renal function (eGFR, and/or advanced CKD stage).

A further embodiment of patients with (chronic) renal impairment (CKD)as described herein relates to type 2 diabetes patients having micro- ormacroalbuminuria; optionally with or without renal function impairment.

A yet further embodiment of patients with (chronic) renal impairment(CKD) as described herein relates to type 2 diabetes patients havingmicroalbuminuria, with renal function impairment.

A yet further embodiment of patients with (chronic) renal impairment(CKD) as described herein relates to type 2 diabetes patients havingmacroalbuminuria, with renal function impairment.

A further embodiment of patients with (chronic) renal impairment (CKD)as described herein relates to type 2 diabetes patients having impairedrenal function such as indicated herein, with or without micro- ormacroalbuminuria, and having a previous macrovascular disease (e.g.myocardial infarction, coronary artery disease, stroke, carotid arterydisease or peripheral artery disease).

In a further embodiment, the patients as described herein are treatedwith a DPP-4 inhibitor (particularly linagliptin) and metformin(particularly in the form of metformin hydrochloride) on top of or inadd-on combination with one or more other (conventional) antidiabeticsand/or an angiotensin converting enzyme (ACE) inhibitor or anangiotensin receptor blocker (ARB).

In a further embodiment, the patients as described herein may be with orat-risk of further (major) (micro- and/or macro-)vascular diseases,complications or events, such as e.g. such patients may be at highvascular risk.

For example, such patients at high vascular risk may have:

-   -   both    -   albuminuria (e.g. micro- or macro-albuminuria)    -   and    -   previous macrovascular (e.g. cardio- or cerebrovascular) disease        (such as e.g. myocardial infarction, coronary artery disease,        (ischemic or haemorrhagic) stroke, carotid artery disease and/or        peripheral artery disease),    -   and/or    -   either    -   (mild or moderate) renal impairment (e.g. CKD stage 1, 2 or 3,        such as CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably        eGFR ≥45-75 mL/min/1.73 m²) with macro-albuminuria,    -   or (moderate [or severe]) renal impairment (e.g. CKD stage 3 [or        4], such as CKD stage 3b (moderate-severe) [or 4 (severe),        preferably eGFR 15-45 mL/min/1.73 m²]), with or without any        albuminuria (such as e.g. with or without micro- or        macro-albuminuria).

In more detail, such a patient at high vascular risk (e.g. at high riskof CV events) may be a patient (preferably diabetic, particularly type 2diabetes patients) as follows:

-   -   with    -   albuminuria (such as e.g. urine albumin creatinine ratio (UACR)        30 mg/g creatinine or ≥30 mg/l (milligram albumin per liter of        urine) or ≥30 μg/min (microgram albumin per minute) or ≥30 mg/24        h (milligram albumin per 24 hours)) and    -   previous macrovascular disease, such as e.g. defined as one or        more of a) to f):    -   a) previous myocardial infarction,    -   b) advanced coronary artery disease,    -   c) high-risk single-vessel coronary artery disease,    -   d) previous ischemic or haemorrhagic stroke,    -   e) presence of carotid artery disease,    -   f) presence of peripheral artery disease,    -   and/or    -   with    -   impaired renal function (e.g. with or without CV        co-morbidities), such as e.g. defined by:    -   impaired renal function (e.g. as defined by MDRD formula) with        an eGFR [15 or] 30-45 mL/min/1.73 m² with any urine albumin        creatinine ratio (UACR), and/or    -   impaired renal function (e.g. as defined by MDRD formula) with        an eGFR ≥45-75    -   mL/min/1.73 m² with an urine albumin creatinine ratio        (UACR) >200 mg/g creatinine or >200 mg/l (milligram albumin per        liter of urine) or >200 μg/min (microgram albumin per minute)        or >200 mg/24 h (milligram albumin per 24 hours).

The present invention relates to a combination or a pharmaceuticalcomposition comprising a certain DPP-4 inhibitor (particularlylinagliptin) and metformin (particularly in the form of metforminhydrochloride) such as for simultaneous, separate or sequential use inthe therapies or treatments described herein.

The present invention also relates to a fixed or free combination orpharmaceutical composition comprising, consisting essentially of or madeof a certain DPP-4 inhibitor (particularly linagliptin) and metformin(particularly in the form of metformin hydrochloride) each as definedherein, and optionally one or more pharmaceutically acceptableauxiliaries (such as e.g. including excipients, stabilizers, carriers orthe like), for medical uses as described herein, such as e.g. forimproving glycemic control and/or for use in treating and/or preventing(including slowing the progression and/or delaying the onset) ofmetabolic diseases, especially type 2 diabetes mellitus and/orconditions related thereto (e.g. diabetic complications, such as e.g.diabetic chronic kidney disease, diabetic nephropathy, micro-ormacroalbuminuria, renal impairment, diabetic retinopathy and/or diabeticneuropathy, and/or a macrovascular complication), such as e.g.

-   -   either as first line therapy, i.e. in type 2 diabetes patients        who have not previously treated with an antihyperglycemic agent        (drug-naïve patients),    -   or as second or third line therapy, i.e. in type 2 diabetes        patients with insufficient glycemic control despite therapy with        one or two conventional antihyperglycemic agents selected from        metformin, sulphonylureas, thiazolidinediones (e.g.        pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or        GLP-1 analogues, and insulin or insulin analogues;    -   including in patients with (chronic) renal disease, renal        dysfunction or renal impairment, particularly in patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        in patients with (chronic) renal impairment of moderate stage        (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate        stage (CKD stage 3a) such as having eGFR levels 45-59, or even        of moderate-to-severe stage such as having eGFR levels 30-44        (CKD stage 3b);    -   optionally in combination with one or more other active        substances, such as e.g. any of those mentioned herein,    -   such as e.g. optionally in combination with one conventional        antihyperglycemic agent selected from sulphonylureas,        thiazolidinediones (e.g. pioglitazone), glinides,        alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and        insulin or insulin analogues, and/or angiotensin converting        enzyme (ACE) inhibitors or an angiotensin receptor blockers        (ARBs).

The present invention also relates to medical uses as described hereinof a pharmaceutical composition comprising a fixed dose combinationformulation of a DPP-4 inhibitor and metformin (particularly in the formof metformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries.

In one embodiment, the present invention also relates to a fixed or freecombination or pharmaceutical composition comprising or consistingessentially of a DPP-4 inhibitor (particularly linagliptin), metformin(particularly in the form of metformin hydrochloride) and optionally oneor more pharmaceutically acceptable auxiliaries, for use in treatingand/or preventing (including slowing the progression and/or delaying theonset) of metabolic diseases, especially type 2 diabetes mellitus and/orconditions related thereto (e.g. diabetic complications), such as e.g.

-   -   either as first line therapy, i.e. in type 2 diabetes patients        who have not previously treated with an antihyperglycemic agent        (drug-naïve patients),    -   or as second or third line therapy, i.e. in type 2 diabetes        patients with insufficient glycemic control despite therapy with        one or two conventional antihyperglycemic agents selected from        metformin, sulphonylureas, thiazolidinediones, glinides,        alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and        insulin or insulin analogues;    -   including in patients with (chronic) renal disease, renal        dysfunction or renal impairment, particularly in patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        in patients with (chronic) renal impairment of moderate stage        (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate        stage (CKD stage 3a) having eGFR levels 45-59, or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b);    -   optionally in combination with one or more other active        substances,    -   such as e.g. optionally in combination with one or more other        antidiabetics such as selected from sulphonylureas,        thiazolidinediones (e.g. pioglitazone), glinides,        alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and        insulin or insulin analogues, and/or an angiotensin converting        enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).

In a particular embodiment, the present invention relates to acombination or pharmaceutical composition comprising a DPP-4 inhibitor(particularly linagliptin), metformin (particularly in the form ofmetformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries, for use in treating and/or preventing (includingslowing the progression and/or delaying the onset) of metabolicdiseases, especially type 2 diabetes mellitus and/or conditions relatedthereto (e.g. diabetic complications, such as e.g. diabetic chronickidney disease, diabetic nephropathy, micro-or macroalbuminuria, renalimpairment, diabetic retinopathy and/or diabetic neuropathy, and/or amacrovascular complication such as a cardio- or cerebrovascular event),in type 2 diabetes patients with insufficient glycemic control despitemono-therapy with metformin;

-   -   wherein the patients have (chronic) renal disease, renal        dysfunction or renal impairment, particularly in patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        in patients with (chronic) renal impairment of moderate stage        (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate        stage (CKD stage 3a) having eGFR levels 45-59, or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b).

In another particular embodiment, the present invention also relates toa combination or pharmaceutical composition comprising a DPP-4 inhibitor(particularly linagliptin), metformin (particularly in the form ofmetformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries, for use in combination with a sulphonylurea intreating and/or preventing (including slowing the progression and/ordelaying the onset) of metabolic diseases, especially type 2 diabetesmellitus and/or conditions related thereto (e.g. diabetic complications,such as e.g. diabetic chronic kidney disease, diabetic nephropathy,micro-or macroalbuminuria, renal impairment, diabetic retinopathy and/ordiabetic neuropathy, and/or a macrovascular complication such as acardio- or cerebrovascular event), in type 2 diabetes patients withinsufficient glycemic control despite dual combination therapy withmetformin and a sulphonylurea;

-   -   wherein the patients have (chronic) renal disease, renal        dysfunction or renal impairment, particularly patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        patients with (chronic) renal impairment of moderate stage (CKD        stage 3, eGFR 30-60), particularly of mild-to-moderate stage        (CKD stage 3a) having eGFR levels 45-59 or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b).

In another particular embodiment, the present invention also relates toa combination or pharmaceutical composition comprising a DPP-4 inhibitor(particularly linagliptin), metformin (particularly in the form ofmetformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries, for use in combination with a thiazolidinedione(e.g. pioglitazone) in treating and/or preventing (including slowing theprogression and/or delaying the onset) of metabolic diseases, especiallytype 2 diabetes mellitus and/or conditions related thereto (e.g.diabetic complications, such as e.g. diabetic chronic kidney disease,diabetic nephropathy, micro-or macroalbuminuria, renal impairment,diabetic retinopathy and/or diabetic neuropathy, and/or a macrovascularcomplication such as a cardio- or cerebrovascular event), in type 2diabetes patients with insufficient glycemic control despite dualcombination therapy with metformin and a thiazolidinedione (e.g.pioglitazone); wherein the patients have (chronic) renal disease, renaldysfunction or renal impairment, particularly patients having chronickidney disease (CKD) such as, e.g., up to stage 3 and/or havingestimated glomerular filtration rate (eGFR; mL/minute/1.73 m²) levelsdown to 45 or even down to 30, such as patients with (chronic) renalimpairment of moderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59 or evenof moderate-to-severe stage having eGFR levels 30-44 (CKD stage 3b).

In another particular embodiment, the present invention also relates toa combination or pharmaceutical composition comprising a DPP-4 inhibitor(particularly linagliptin), metformin (particularly in the form ofmetformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries, for use in combination with an insulin (e.g.basal insulin) in treating and/or preventing (including slowing theprogression and/or delaying the onset) of metabolic diseases, especiallytype 2 diabetes mellitus and/or conditions related thereto (e.g.diabetic complications, such as e.g. diabetic chronic kidney disease,diabetic nephropathy, micro-or macroalbuminuria, renal impairment,diabetic retinopathy and/or diabetic neuropathy, and/or a macrovascularcomplication such as a cardio- or cerebrovascular event), in type 2diabetes patients with insufficient glycemic control despite dualcombination therapy with metformin and an insulin (e.g. basal insulin);

-   -   wherein the patients have (chronic) renal disease, renal        dysfunction or renal impairment, particularly patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        patients with (chronic) renal impairment of moderate stage (CKD        stage 3, eGFR 30-60), particularly of mild-to-moderate stage        (CKD stage 3a) having eGFR levels 45-59 or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b).

In another particular embodiment, the present invention also relates toa combination or pharmaceutical composition comprising a DPP-4 inhibitor(particularly linagliptin), metformin (particularly in the form ofmetformin hydrochloride) and optionally one or more pharmaceuticallyacceptable auxiliaries, for use in treating and/or preventing (includingslowing the progression and/or delaying the onset) of metabolicdiseases, especially type 2 diabetes mellitus and/or conditions relatedthereto (e.g. diabetic complications), in drug-naïve type 2 diabetespatients (e.g. as first line therapy), such as e.g. as early or initialcombination therapy;

-   -   wherein the patients have (chronic) renal disease, renal        dysfunction or renal impairment, particularly patients having        chronic kidney disease (CKD) such as, e.g., up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        patients with (chronic) renal impairment of moderate stage (CKD        stage 3, eGFR 30-60), particularly of mild-to-moderate stage        (CKD stage 3a) having eGFR levels 45-59 or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b).

The present invention further provides the use of a combination orpharmaceutical composition comprising a DPP-4 inhibitor (particularlylinagliptin), metformin (particularly in the form of metforminhydrochloride) and optionally one or more pharmaceutically acceptableauxiliaries, for the manufacture of a medicament for treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications), e.g. asfirst, second or third line therapy as described herein, including inthe patients as described herein.

The present invention further relates to a pharmaceutical packagecomprising a pharmaceutical composition as defined herein and optionallyinstructions for its use, optionally in combination with one or moreother active substances, in the treatment and/or prevention of metabolicdiseases, particularly type 2 diabetes mellitus and/or conditionsrelated thereto (e.g. diabetic complications), such as e.g. indrug-naïve patients or in patients with insufficient glycemic controldespite therapy with one or two conventional antihyperglycemic agentsselected from metformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues; preferably in patients with (chronic) renal disease,renal dysfunction or renal impairment, particularly in patients havingchronic kidney disease (CKD) such as, e.g., up to stage 3 and/or havingestimated glomerular filtration rate (eGFR; mL/minute/1.73 m²) levelsdown to 45 or even down to 30, such as in patients with (chronic) renalimpairment of moderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59,or even of moderate-to-severe stage such as having eGFR levels 30-44(CKD stage 3b).

The present invention further relates to a medicament for use in thetreatment and/or prevention of metabolic diseases, particularly type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), such as e.g. in drug-naïve patients or in patients withinsufficient glycemic control despite therapy with one or twoconventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues;preferably in patients with (chronic) renal disease, renal dysfunctionor renal impairment, particularly in patients having chronic kidneydisease (CKD) such as, e.g., to stage 3 and/or having estimatedglomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45or even down to 30, such as in patients with (chronic) renal impairmentof moderate stage (CKD stage 3, eGFR 30-60), particularly ofmild-to-moderate stage (CKD stage 3a) such as having eGFR levels 45-59,or even of moderate-to-severe stage such as having eGFR levels 30-44(CKD stage 3b); said medicament comprising a pharmaceutical compositioncomprising a DPP-4 inhibitor (particularly linagliptin), metformin(particularly in the form of metformin hydrochloride) and optionally oneor more pharmaceutically acceptable auxiliaries; optionally incombination with one or more other active substances, such as e.g. anyof those mentioned herein, such as e.g. for separate, sequential,simultaneous, concurrent or chronologically staggered use of the activeingredients.

The present invention further provides a method of treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications), such ase.g. in drug-naïve patients (e.g. as first line therapy) or in patientswith insufficient glycemic control despite therapy with one or twoconventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues(e.g. as second or third line therapy); preferably in patients with(chronic) renal disease, renal dysfunction or renal impairment,particularly in patients having chronic kidney disease (CKD) such ase.g. up to stage 3 and/or having estimated glomerular filtration rate(eGFR; mL/minute/1.73 m²) levels down to 45 or even down to 30, such asin patients with (chronic) renal impairment of moderate stage (CKD stage3, eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)such as having eGFR levels 45-59, or even of moderate-to-severe stagesuch as having eGFR levels 30-44 (CKD stage 3b); said method comprisingadministering to a subject in need thereof (particularly a humanpatient) an effective amount of a pharmaceutically compositioncomprising a DPP-4 inhibitor (particularly linagliptin), metformin(particularly in the form of metformin hydrochloride) and optionally oneor more pharmaceutically acceptable auxiliaries, optionally alone or incombination, such as e.g. separately, sequentially, simultaneously,concurrently or chronologically staggered, with an effective amount ofone or more other active substances, such as e.g. any of those mentionedherein.

In a particular embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), in drug-naïve patients (e.g. as first line therapy);including in patients with (chronic) renal disease, renal dysfunction orrenal impairment, particularly in patients having chronic kidney disease(CKD) such as e.g. up to stage 3 and/or having estimated glomerularfiltration rate (eGFR; mL/minute/1.73 m²) levels down to 45 or even downto 30, such as in patients with (chronic) renal impairment of moderatestage (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage(CKD stage 3a) having eGFR levels 45-59, or even of moderate-to-severestage having eGFR levels 30-44 (CKD stage 3b); said method comprisingadministering to a subject in need thereof (particularly a humanpatient) an effective amount of a pharmaceutically composition of aDPP-4 inhibitor (particularly linagliptin) and metformin (particularlyin the form of metformin hydrochloride) such as described herein.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and/or conditions related thereto (e.g.diabetic complications), in patients with insufficient glycemic controldespite mono-therapy with metformin (e.g. as second line therapy);including in patients with (chronic) renal disease, renal dysfunction orrenal impairment, particularly in patients having chronic kidney disease(CKD) such as e.g. up to stage 3 and/or having estimated glomerularfiltration rate (eGFR; mL/minute/1.73 m²) levels down to 45 or even downto 30, such as in patients with (chronic) renal impairment of moderatestage (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage(CKD stage 3a) having eGFR levels 45-59, or even of moderate-to-severestage having eGFR levels 30-44 (CKD stage 3b); said method comprisingadministering to a subject in need thereof (particularly a humanpatient) an effective amount of a pharmaceutically composition of aDPP-4 inhibitor (particularly linagliptin) and metformin (particularlyin the form of metformin hydrochloride) such as described herein.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and/or conditions related thereto (e.g.diabetic complications), in patients with insufficient glycemic controldespite dual combination therapy with metformin and a thiazolidinedione(e.g. as third line therapy); including in patients with (chronic) renaldisease, renal dysfunction or renal impairment, particularly in patientshaving chronic kidney disease (CKD) such as e.g. up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45 or even down to 30, such as in patients with (chronic)renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) having eGFR levels45-59, or even of moderate-to-severe stage having eGFR levels 30-44 (CKDstage 3b); said method comprising administering to a subject in needthereof (particularly a human patient) an effective amount of apharmaceutically composition of a DPP-4 inhibitor (particularlylinagliptin) and metformin (particularly in the form of metforminhydrochloride) such as described herein, and a thiazolidinedione.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and/or conditions related thereto (e.g.diabetic complications), in patients with insufficient glycemic controldespite dual combination therapy with metformin and a sulphonylurea(e.g. as third line therapy); including in patients with (chronic) renaldisease, renal dysfunction or renal impairment, particularly in patientshaving chronic kidney disease (CKD) such as e.g. up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45 or even down to 30, such as in patients with (chronic)renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) having eGFR levels45-59, or even of moderate-to-severe stage having eGFR levels 30-44 (CKDstage 3b); said method comprising administering to a subject in needthereof (particularly a human patient) an effective amount of apharmaceutically composition of a DPP-4 inhibitor (particularlylinagliptin) and metformin (particularly in the form of metforminhydrochloride) such as described herein, and a sulphonylurea.

In a further embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), in patients with insufficient glycemic control despitedual combination therapy with metformin and insulin or insulin analog;including in patients with (chronic) renal disease, renal dysfunction orrenal impairment, particularly in patients having chronic kidney disease(CKD) such as e.g. up to stage 3 and/or having estimated glomerularfiltration rate (eGFR; mL/minute/1.73 m²) levels down to 45 or even downto 30, such as in patients with (chronic) renal impairment of moderatestage (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage(CKD stage 3a) having eGFR levels 45-59, or even of moderate-to-severestage having eGFR levels 30-44 (CKD stage 3b); said method comprisingadministering to a subject in need thereof (particularly a humanpatient) an effective amount of a pharmaceutically composition of aDPP-4 inhibitor (particularly linagliptin) and metformin (particularlyin the form of metformin hydrochloride) such as described herein, andinsulin or insulin analog.

In a further embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), in patients treated with insulin or insulin analog;

-   -   including in patients with (chronic) renal disease, renal        dysfunction or renal impairment, particularly in patients having        chronic kidney disease (CKD) such as e.g. up to stage 3 and/or        having estimated glomerular filtration rate (eGFR;        mL/minute/1.73 m²) levels down to 45 or even down to 30, such as        in patients with (chronic) renal impairment of moderate stage        (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate        stage (CKD stage 3a) having eGFR levels 45-59, or even of        moderate-to-severe stage having eGFR levels 30-44 (CKD stage        3b); said method comprising administering to a subject in need        thereof (particularly a human patient) an effective amount of a        pharmaceutically composition of a DPP-4 inhibitor (particularly        linagliptin) and metformin (particularly in the form of        metformin hydrochloride) such as described herein, thereby        replacing said insulin or insulin analog (i.e. switching from        insulin therapy to a BI 1356 & metformin combination according        to this invention).

Examples of metabolic disorders or diseases amenable by the therapy ofthis invention may include, without being limited to, type 1 diabetes,type 2 diabetes, diabetic complications (e.g. as described herein),impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG),hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia,latent autoimmune diabetes in adults (LADA), overweight, obesity,dyslipidemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, hyperNEFA-emia, fasting or postprandialhyperlipidemia such as postprandial lipemia (e.g. postprandialhypertriglyceridemia), hypertension, atherosclerosis, endothelialdysfunction, osteoporosis, chronic systemic inflammation, non alcoholicfatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy,polycystic ovarian syndrome, and/or metabolic syndrome.

The present invention further relates to a certain DPP-4 inhibitor(preferably linagliptin) in combination with metformin (particularly inthe form of metformin hydrochloride), and optionally in combination withone or more other active agents, for use in at least one of thefollowing methods:

-   -   preventing, slowing the progression of, delaying the onset of or        treating a metabolic disorder or disease, such as e.g. type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance (IGT), impaired fasting blood glucose (IFG),        hyperglycemia, postprandial hyperglycemia, postabsorptive        hyperglycemia, latent autoimmune diabetes in adults (LADA),        overweight, obesity, dyslipidemia, hyperlipidemia,        hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia,        postprandial lipemia (e.g. postprandial hypertriglyceridemia),        hypertension, atherosclerosis, endothelial dysfunction,        osteoporosis, chronic systemic inflammation, non alcoholic fatty        liver disease (NAFLD), retinopathy, neuropathy, nephropathy,        polycystic ovarian syndrome, and/or metabolic syndrome;    -   improving and/or maintaining glycemic control and/or for        reducing of fasting plasma glucose, of postprandial plasma        glucose, of postabsorptive plasma glucose and/or of glycosylated        hemoglobin HbA1c, or preventing, reducing the risk of, slowing        the progression of, delaying the onset of or treating worsening        or deterioration of glycemic control, need for insulin therapy        or elevated HbA1c despite treatment;    -   preventing, slowing, delaying the onset of or reversing        progression from pre-diabetes, impaired glucose tolerance (IGT),        impaired fasting blood glucose (IFG), insulin resistance and/or        from metabolic syndrome to type 2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying the onset of or treating of complications of diabetes        mellitus such as micro- and macrovascular diseases, such as        nephropathy, micro- or macroalbuminuria, proteinuria,        retinopathy, cataracts, neuropathy, learning or memory or        cognitive impairment or decline, neurodegenerative or cognitive        disorders (e.g. dementia), cardio- or cerebrovascular diseases,        tissue ischaemia, diabetic foot or ulcus, atherosclerosis,        hypertension, endothelial dysfunction, myocardial infarction,        acute coronary syndrome, unstable angina pectoris, stable angina        pectoris, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders, vascular restenosis,        and/or stroke;    -   reducing body weight and/or body fat and/or liver fat and/or        intra-myocellular fat or preventing an increase in body weight        and/or body fat and/or liver fat and/or intra-myocellular fat or        facilitating a reduction in body weight and/or body fat and/or        liver fat and/or intra-myocellular fat;    -   preventing, slowing, delaying the onset of or treating the        degeneration of pancreatic beta cells and/or the decline of the        functionality of pancreatic beta cells and/or for improving,        preserving and/or restoring the functionality of pancreatic beta        cells and/or stimulating and/or restoring or protecting the        functionality of pancreatic insulin secretion;    -   preventing, slowing, delaying the onset of or treating non        alcoholic fatty liver disease (NAFLD) including hepatic        steatosis, non-alcoholic steatohepatitis (NASH) and/or liver        fibrosis (such as e.g. preventing, slowing the progression,        delaying the onset of, attenuating, treating or reversing        hepatic steatosis, (hepatic) inflammation and/or an abnormal        accumulation of liver fat);    -   preventing, slowing the progression of, delaying the onset of or        treating type 2 diabetes with failure to conventional        antidiabetic mono- or combination therapy;    -   achieving a reduction in the dose of conventional antidiabetic        medication (e.g. of a sulphonylurea or an insulin) required for        adequate therapeutic effect;    -   reducing the risk for adverse effects associated with        conventional antidiabetic medication (e.g. hypoglycemia or        weight gain, such as associated with e.g. insulin or        sulphonylurea medication); and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;

in a patient in need thereof (such as e.g. a patient as describedherein), particularly

-   -   in patients with (chronic) renal disease, renal dysfunction or        renal impairment, particularly in patients having chronic kidney        disease (CKD) such as e.g. up to stage 3 and/or having estimated        glomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down        to 45, or even down to 30, such as in patients with (chronic)        renal impairment of moderate stage (CKD stage 3, eGFR 30-60),        particularly of mild-to-moderate stage (CKD stage 3a) such as        having eGFR levels 45-59 or of moderate-to-severe stage such as        having eGFR levels 30-44 (CKD stage 3b.

Such therapy according to this invention (e.g. as described hereinaboveor hereinbelow in further detail) may include treatment with suchcertain DPP-4 inhibitor (preferably linagliptin, optionally incombination with one or more other active agents) over a lengthy period,such as described in more detail (duration of treatment) herein.

In certain embodiments, the therapy or prophylaxis according to thepresent invention (e.g. such as described hereinabove and hereinbelow)may include duration of treatment with a certain DPP-4 inhibitor,particularly linagliptin (preferably 5 mg per day, administered orally,in combination with metformin (and optionally in combination with one ormore other active substances, e.g. such as those described herein) overa lengthy period (such as e.g. at least 1-6 years, >/=2 years, or 3-7years such as 3-4 years, 3-5 years, 3-6 years, 4-5 years, 4-6 years, 5-6years or 5-7 years, preferably at least 48 months, more preferably atleast 3 years); such as e.g. to provide a long term effect orimprovement on (cardio)vascular and/or renal (microvascular) safety,morbidity and/or mortality (e.g. including effect on cognitiveimpairment) according to the present invention; such as e.g. in patients(e.g. diabetic patients, especially type 2 diabetes patients) asdescribed herein.

For example, the therapy or prophylaxis according to the presentinvention (e.g. such as described hereinabove and hereinbelow) mayinclude duration of treatment with a certain DPP-4 inhibitor,particularly linagliptin (preferably 5 mg per day, administered orally),in combination with metformin (and optionally in combination with one ormore other active substances, e.g. such as those described herein) overa lengthy period, preferably at least 48 months, more preferably atleast 3 years (such as e.g. at least 3-4 years, or at least 5-6 years).

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6 % HbA1c.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 90-130 mg/dL (or 70-130 mg/dL) or <110 mg/dL, and oftwo-hour postprandial plasma glucose are <180 mg/dL or <140 mg/dL.

Within the meaning of this invention, inadequate or insufficientglycemic control means in particular a condition wherein patients showHbA1c values above 6.5%, in particular above 7.0%, even more preferablyabove 7.5%, especially above 8%. An embodiment of patients withinadequate or insufficient glycemic control include, without beinglimited to, patients having a HbA1c value from 6.5 to 10% (or, inanother embodiment, from 7.5 to 10%; or, in another embodiment, from 7.5to 11%, or, in another embodiment, from 6.5 to 8.5% or, in anotherembodiment, from 6.5 to 7.5%). A special sub-embodiment of inadequatelycontrolled patients refers to patients with poor glycemic controlincluding, without being limited, patients having a HbA1c value 9%.

In an embodiment, diabetes patients within the meaning of this inventionmay include patients who have not previously been treated with anantidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In certainembodiments of the therapies of this invention, the DPP-4 inhibitor(preferably linagliptin) may be used alone or in combination with one ormore other antidiabetics in such patients. In another embodiment,diabetes patients within the meaning of this invention may includepatients pre-treated with conventional antidiabetic backgroundmedication, such as e.g. patients with advanced or late stage type 2diabetes mellitus (including patients with failure to conventionalantidiabetic therapy), such as e.g. patients with inadequate glycemiccontrol on one, two or more conventional oral and/or non-oralantidiabetic drugs as defined herein, such as e.g. patients withinsufficient glycemic control despite (mono-)therapy with metformin, athiazolidinedione (particularly pioglitazone), a sulphonylurea, aglinide, GLP-1 or GLP-1 analogue, insulin or insulin analogue, or anα-glucosidase inhibitor, or despite dual combination therapy withmetformin/sulphonylurea, metformin/thiazolidinedione (particularlypioglitazone), sulphonylurea/α-glucosidase inhibitor,pioglitazone/sulphonylurea, metformin/insulin, pioglitazone/insulin orsulphonylurea/insulin. Thus, in an embodiment, the therapies describedherein may be used in patients experienced with therapy, e.g. withconventional oral and/or non-oral antidiabetic mono- or dual or triplecombination medication as mentioned herein. In certain embodiments ofthe therapies of this invention, in such patients the DPP-4 inhibitor(preferably linagliptin) may be used on top of or added on the existingor ongoing conventional oral and/or non-oral antidiabetic mono- or dualor triple combination medication with which such patients arepre-treated or experienced.

For example, a diabetes patient (particularly type 2 diabetes patient,with insufficient glycemic control) of this invention may betreatment-naïve or pre-treated with one or more (e.g. one or two)conventional antidiabetic agents selected from metformin,thiazolidinediones (particularly pioglitazone), sulphonylureas,glinides, α-glucosidase inhibitors (e.g. acarbose, voglibose), andinsulin or insulin analogues, such as e.g. pre-treated or experiencedwith:

-   -   metformin, α-glucosidase inhibitor, sulphonylurea or glinide        monotherapy, or metformin plus α-glucosidase inhibitor,        metformin plus sulphonylurea, metformin plus glinide,        α-glucosidase inhibitor plus sulphonylurea, or α-glucosidase        inhibitor plus glinide dual combination therapy.

In certain embodiments relating to such treatment-naïve patients, theDPP-4 inhibitor (preferably linagliptin) may be used as monotherapy, oras initial combination therapy such as e.g. with metformin, athiazolidinedione (particularly pioglitazone), a sulphonylurea, aglinide, an α-glucosidase inhibitor (e.g. acarbose, voglibose), GLP-1 orGLP-1 analogue, or insulin or insulin analogue; preferably asmonotherapy.

In certain embodiments relating to such patients pre-treated orexperienced with one or two conventional antidiabetic agents, the DPP-4inhibitor (preferably linagliptin) may be used as add-on combinationtherapy, i.e. added to an existing or background therapy with the one ortwo conventional antidiabetics in patients with insufficient glycemiccontrol despite therapy with the one or more conventional antidiabeticagents, such as e.g. as add-on therapy to one or more (e.g. one or two)conventional antidiabetics selected from metformin, thiazolidinediones(particularly pioglitazone), sulphonylureas, glinides, α-glucosidaseinhibitors (e.g. acarbose, voglibose), GLP-1 or GLP-1 analogues, andinsulin or insulin analogues, such as e.g.:

-   -   as add-on therapy to metformin, to a α-glucosidase inhibitor, to        a sulphonylurea or to a glinide;    -   or as add-on therapy to metformin plus α-glucosidase inhibitor,        to metformin plus sulphonylurea, to metformin plus glinide, to        α-glucosidase inhibitor plus sulphonylurea, or to α-glucosidase        inhibitor plus glinide;    -   or as add-on therapy to an insulin, with or without metformin, a        thiazolidinedione (particularly pioglitazone), a sulphonylurea,        a glinide or an α-glucosidase inhibitor (e.g. acarbose,        voglibose).

An embodiment of the patients which may be amenable to the therapies ofthis invention may include, without being limited, those diabetespatients for whom normal metformin therapy is less appropriate, such ase.g. those diabetes patients who need reduced dose metformin therapy dueto reduced tolerability, intolerability or contraindication againstmetformin or due to impaired/reduced renal function (e.g. elderlypatients, such as e.g. ≥60-65 years).

In a further embodiment, the patient described herein is a subjecthaving diabetes (e.g. type 1 or type 2 diabetes or LADA, particularlytype 2 diabetes).

In particular, the subject within this invention may be a human, e.g.human child, a human adolescent or, particularly, a human adult.

In further particular, the subject within this invention is a human type2 diabetes patient.

In certain embodiments, the subject within this invention is a (human)type 2 diabetes patient in early diabetes stage or, particularly, inadvanced diabetes stage. In an embodiment, the patient has long-standingtype 2 diabetes (e.g. >10 years) and/or is treated with insulin.

In further certain embodiments, the subject within this invention is a(human) type 2 diabetes patient in early CKD stage or, particularly, inadvanced CKD stage.

The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-4 inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

A particularly preferred DPP-4 inhibitor to be emphasized within thepresent invention is1-[(4-methyl-quinazolin-2-Amethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as linagliptinor BI 1356).

The DPP-4 inhibitor of this invention may be selected from the groupconsisting of linagliptin, sitagliptin, vildagliptin, alogliptin,saxagliptin, teneligliptin, anagliptin, gemigliptin and dutogliptin, ora pharmaceutically acceptable salt of one of the herein mentioned DPP-4inhibitors, or a prodrug thereof.

DPP-4 is analogous to CD26 a T-cell antigene which plays a role inT-cell activation and immuno-modulation. Further, some substrates ofDPP-4 (beyond incretins) may have potential cardio-renal effects.

Furthermore, linagliptin, a selective DPP-4 inhibitor may qualify forthe instant purposes with certain anti-oxidative and/oranti-inflammatory features.

Linagliptin may further have a direct impact on the integrity of theendothelium and podocytes of the glomerula and the proximal tubularcells of the kidney as well as on endothelial function and linagliptinhas a relatively high tissue distribution, including in the kidney.

Further, samples from human kidneys indicate that proteinuric humandiseases (such as e.g. diabetic nephropathy or nephrotic syndrome) seemto be characterized by an upregulation of glomerular DPP-4.

Moreover, linagliptin may further qualify for the instant purposes byantidiabetic and anti-albuminuric effects/usability preferably in type 2diabetes patients, with micro- or macroalbuminuria (e.g. 30-3000 mg/gcreatinine), preferably on top of current standard treatment fordiabetic nephropathy (e.g. ACE inhibitor or ARB).

It is further noteworthy that most major DPP-4 inhibitors (e.g.sitagliptin, saxagliptin, alogliptin and vildagliptin) require doseadjustment/reduction in the renally impaired (CKD) population.

The DPP-4 inhibitor linagliptin, however, is unique in being secretedvia the bile and does not require adjustment of dose with decliningrenal function.

Additionally, the DPP-4 inhibitor linagliptin can exert anti-fibroticeffects, such as on kidney fibrosis.

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at dose levels <100 mg or <70 mgper patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg (if required, divided into 1to 4 single doses, particularly 1 or 2 single doses, which may be of thesame size), particularly from 1 mg to 5 mg (more particularly 5 mg), perpatient per day, preferentially, administered orally once-daily, morepreferentially, at any time of day, administered with or without food.Thus, for example, the therapeutic daily oral dose 5 mg BI 1356 can begiven in a once daily dosing regimen (i.e. 5 mg BI 1356 once daily) orin a twice daily dosing regimen (i.e. 2.5 mg BI 1356 twice daily), atany time of day, with or without food.

The present invention further relates to a pharmaceutical composition orcombination comprising or consisting essentially of a certain DPP-4inhibitor (particularly linagliptin) and metformin (particularly in theform of metformin hydrochloride), optionally in combination oralternation with one or more other therapeutic agents, each as describedherein, such as e.g. for simultaneous, sequential or separate medicaluse in therapy or prophylaxis as described herein.

Within this invention it is to be understood that the combinations orcombined uses according to this invention may envisage the simultaneous,sequential or separate administration of the active components.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits, or other administration, application ordosage forms) and uses, such as e.g. the simultaneous, sequential orseparate use of the components.

The combined administration or application of this invention may takeplace by administering the therapeutic components together, such as e.g.by administering them simultaneously in one single or in two separateformulations. Alternatively, the administration may take place byadministering the therapeutic components sequentially, such as e.g.successively in two separate formulations.

For the combination therapy of this invention the therapeutic componentsmay be administered separately (which implies that they are formulatedseparately) or formulated altogether (which implies that they areformulated in the same preparation). Hence, the administration of oneelement of the combination of the present invention may be prior to,concurrent to, or subsequent to the administration of the other elementof the combination.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

Unless otherwise noted, monotherapy may refer to first line therapy(e.g. therapy of patients with insufficient glycemic control by diet andexercise alone, such as e.g. drug-naive patients, typically patientsearly after diagnosis and/or who have not been previously treated withan antidiabetic agent, and/or patients ineligible for metformin therapysuch as e.g. patients for whom metformin therapy is contraindicated,such as e.g. due to renal impairment, or inappropriate, such as e.g. dueto intolerance).

Unless otherwise noted, add-on combination therapy may refer to secondline or third line therapy (e.g. therapy of patients with insufficientglycemic control despite (diet and exercise plus) therapy with one ortwo conventional antidiabetic agents, typically patients who arepre-treated with one or two antidiabetic agents, such as e.g. patientswith such existing antidiabetic background medication).

Unless otherwise noted, initial combination therapy may refer to firstline therapy (e.g. therapy of patients with insufficient glycemiccontrol by diet and exercise alone, such as e.g. drug-naive patients,typically patients early after diagnosis and/or who have not beenpreviously treated with an antidiabetic agent).

A DPP-4 inhibitor according to the invention is preferably administeredorally.

In one embodiment, pharmaceutical compositions or fixed dosecombinations of a DPP-4 inhibitor (particularly linagliptin) andmetformin (particularly in the form of metformin hydrochloride) such asdescribed herein include, without being limited to, such compositionswhich comprise immediate release metformin and the DPP-4 inhibitor(preferably as an immediate release component). In connection with suchcompositions, further reference is made for example to WO 2009/121945,the disclosure of which is incorporated herein. Particular reference ismade to those tablet forms which are described in more detail in theexample section of WO 2009/121945; the mono-layer tablet hereby beingpreferred.

In another embodiment, pharmaceutical compositions or fixed dosecombinations of a DPP-4 inhibitor (particularly linagliptin) andmetformin (particularly in the form of metformin hydrochloride) such asdescribed herein include, without being limited to, such compositionswhich comprise controlled or sustained (e.g. slow or extended) releasemetformin and the DPP-4 inhibitor (preferably as an immediate releasecomponent). Examples of such compositions include, without beinglimited, drug (DPP-4 inhibitor)-coated tablets (which may be optionallyover-coated with a non-functional film-coat), e.g. compositionscomprising i) an extended release core comprising metformin and one ormore suitable excipients and ii) a (preferably immediate release)film-coating comprising DPP-4 inhibitor (e.g. such as film-coat layer).In connection with such compositions, further reference is made forexample to WO 2012/120040, WO 2013/131967 and PCT/EP2015074030, thedisclosures of which are incorporated herein. Particular reference ismade to the tablet forms as described in more detail in the examplesection of PCT/EP2015074030. Examples of slow release may include,without being limited, a metformin composition (e.g. as tablet core)where metformin is released at a rate where the peak plasma levels ofmetformin are typically achieved about 8-22 h after administration.

In more detailed example, a pharmaceutical composition as mentionedherein comprises a certain DPP-4 inhibitor (particularly linagliptin)and metformin (particularly in the form of metformin hydrochloride), andoptionally one or more pharmaceutically acceptable auxiliaries.

Pharmaceutically acceptable auxiliaries for the pharmaceuticalcompositions as described herein may comprise a stabilizer, such as e.g.arginine, particularly L-arginine.

Particularly, a pharmaceutical composition as described herein compriseslinagliptin and metformin (particularly in the form of metforminhydrochloride), L-arginine (such as e.g. as inactive ingredient or asstabilizer), and optionally one or more further pharmaceuticallyacceptable auxiliaries or excipients.

Pharmaceutically acceptable auxiliaries or excipients mentioned hereinmay comprise optionally in addition to L-arginine other auxiliaries suchas e.g. one or more fillers, one or more diluents, one or more binders,one or more lubricants, one or more release agents, one or moredisintegrants, one or more breakdown agents, one or more flow agents,one or more coating agents, one or more plasticizers, one or morepigments, etc.

In an embodiment, a pharmaceutical composition as described hereincomprises linagliptin (e.g. in an amount of 2.5 mg, such as for twicedaily administration, or in an amount of 5 mg, such as for once dailyadministration) and metformin (particularly in the form of metforminhydrochloride; e.g. in an amount of 500, 750, 850 or 1000 mg; e.g. inimmediate release formulation or in extended release formulation),L-arginine (particularly as stabilizer) and optionally one or more otherauxiliaries.

In an embodiment, a pharmaceutical composition as described hereincomprises linagliptin (e.g. in an amount of 2.5 mg, particularly inimmediate release formulation such as for twice daily administration),metformin (particularly metformin hydrochloride, e.g. in an amount of500, 850 or 1000 mg, particularly in immediate release formulation),L-arginine (particularly as stabilizer), a filler (e.g. maize starch), abinder (e.g. copovidone), and a lubricant (e.g. magnesium stearate) andoptionally a flow agent (e.g. anhydrous colloidal silicon dioxide).

In another embodiment of the present invention the tablets mentionedherein include for example single-layer, double-layer or triple-layertablets, coated core tablets, film-coated tablets, etc.

Typical dosage strengths of the dual fixed dose combination (tablet) oflinagliptin/metformin IR (immediate release) are 2.5/500 mg, 2.5/850 mgand 2.5/1000 mg (linagliptin/metformin hydrochloride), which may beadministered twice a day.

In a particular embodiment, for use in renally impaired patientsaccording to the present invention, especially for use in patients with(chronic) renal impairment of mild-to-moderate stage (CKD stage 3a) suchas having eGFR levels 45-59 or of moderate-to-severe stage such ashaving eGFR levels 30-44 (CKD stage 3b), a particular dosage strength oflinagliptin/metformin IR (immediate release) is 2.5/500 mg(linagliptin/metformin hydrochloride), administered twice daily.

Typical dosage strengths of the dual fixed dose combination (tablet) oflinagliptin/metformin XR (extended release) are 5/1000 mg(linagliptin/metformin hydrochloride), which may be administered as onetablet once a day (preferably to be taken in the evening preferably withmeal), or 2.5/750 and 2.5/1000 (linagliptin/metformin hydrochloride),which may be administered as two tablets once a day (preferably to betaken in the evening preferably with meal).

In a further embodiment, for use in renally impaired patients accordingto the present invention, especially for use in patients with (chronic)renal impairment of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59 or of moderate-to-severe stage such as having eGFRlevels 30-44 (CKD stage 3b), a particular dosage strength oflinagliptin/metformin XR (extended release) is 5/1000 mg(linagliptin/metformin hydrochloride), administered once daily.

In a particular embodiment, for use in renally impaired patientsaccording to the present invention, especially for use in patients with(chronic) renal impairment of mild-to-moderate stage (CKD stage 3a) suchas having eGFR levels 45-59 or of moderate-to-severe stage such ashaving eGFR levels 30-44 (CKD stage 3b), the maximum daily dose may be1000 mg metformin hydrochloride, preferably given as two divided doses,such as e.g. 500 mg BID.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg or 3000 mg per day using various dosing regimens fromabout 100 mg to 500 mg or 200 mg to 850 mg (1-3 times a day), or about300 mg to 1000 mg once or twice a day, or delayed-release metformin indoses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once ortwice a day or about 500 mg to 2000 mg once a day. Particular dosagestrengths may be 250, 500, 625, 750, 850 and 1000 mg of metforminhydrochloride.

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor or pharmaceutical combination or composition according to thisinvention is combined with active substances customary for therespective disorders, such as e.g. one or more active substancesselected from among the other antidiabetic substances, especially activesubstances that lower the blood sugar level or the lipid level in theblood, raise the HDL level in the blood, lower blood pressure or areindicated in the treatment of atherosclerosis or obesity.

The DPP-4 inhibitors or pharmaceutical combinations or compositionsmentioned herein—besides their use on their own—may also be used inconjunction with other active substances, by means of which improvedtreatment results can be obtained. Such a combined treatment may begiven as a free combination of the substances or in the form of a fixedcombination, for example in a tablet or capsule. Pharmaceuticalformulations of the combination partner needed for this may either beobtained commercially as pharmaceutical compositions or may beformulated by the skilled man using conventional methods. The activesubstances which may be obtained commercially as pharmaceuticalcompositions are described in numerous places in the prior art, forexample in the list of drugs that appears annually, the “Rote Liste®” ofthe federal association of the pharmaceutical industry, or in theannually updated compilation of manufacturers' information onprescription drugs known as the “Physicians' Desk Reference”.

Examples of antidiabetic combination partners (such as beyond metformin)are sulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; mitiglinide; thiazolidinediones such as rosiglitazone andpioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gammaagonists such as e.g. rivoglitazone, mitoglitazone, INT-131 andbalaglitazone; PPAR-gamma antagonists; PPAR-gamma/alpha modulators suchas tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297;PPAR-gamma/alpha/delta modulators such as e.g. lobeglitazone;AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2)inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors;pancreatic beta cell GCRP agonists such as GPR119 agonists(SMT3-receptor-agonists); 11B-HSD-inhibitors; FGF19 agonists oranalogues; alpha-glucosidase blockers such as acarbose, voglibose andmiglitol; alpha2-antagonists; insulin and insulin analogues such ashuman insulin, insulin lispro, insulin glusilin, r-DNA-insulinaspart,NPH insulin, insulin detemir, insulin degludec, insulin tregopil,insulin zinc suspension and insulin glargin; Gastric inhibitory Peptide(GIP); amylin and amylin analogues (e.g. pramlintide or davalintide);GLP-1 and GLP-1 analogues such as Exendin-4, e.g. exenatide, exenatideLAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (aPEGylated version of GLP-1), dulaglutide (LY-2189265), semaglutide oralbiglutide; SGLT2-inhibitors such as e.g. dapagliflozin, sergliflozin(KGT-1251), atigliflozin, canagliflozin, ipragliflozin, luseogliflozinor tofogliflozin; inhibitors of protein tyrosine-phosphatase (e.g.trodusquemine); inhibitors of glucose-6-phosphatase;fructose-1,6-bisphosphatase modulators; glycogen phosphorylasemodulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976)or of serine/threonine kinases; glucokinase/regulatory proteinmodulators incl. glucokinase activators; glycogen synthase kinaseinhibitors; inhibitors of the SH2-domain-containing inositol5-phosphatase type 2 (SHIP2); IKK inhibitors such as high-dosesalicylate; JNK1 inhibitors; protein kinase C-theta inhibitors; beta 3agonists such as ritobegron, YM 178, solabegron, talibegron, N-5984,GRC-1087, rafabegron, FMP825; aldosereductase inhibitors such as AS3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809,and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitors;GPR40 modulators such as e.g.[(35)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists(bromocriptine mesylate [Cycloset]);4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuinstimulants; and other DPP IV inhibitors.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (up to 40mg divided twice) a day (typical dosage strengths are 5 and 10 mg), orextended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once aday (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals (up to300 mg/day, typical dosage strengths are 25, 50 and 100 mg). Miglitol isusually given in doses from 25 to 100 mg with meals (up to 300 mg/day,typical dosage strengths are 25, 50 and 100 mg).

Conventional antidiabetics and antihyperglycemics typically used inmono- or dual or triple (add-on or initial) combination therapy mayinclude, without being limited to, metformin, sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 andGLP-1 analogues, as well as insulin and insulin analogues, such as e.g.those agents indicated herein by way of example, including combinationsthereof.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox;

PPAR-alpha agonists; PPAR-delta agonists such as e.g.{4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid; PPAR-alpha/delta agonists; inhibitors of acyl-coenzymeA:cholesterolacyltransferase (ACAT; EC 2.3.1.26) such as avasimibe;cholesterol resorption inhibitors such as ezetimib; substances that bindto bile acid, such as cholestyramine, colestipol and colesevelam;inhibitors of bile acid transport; HDL modulating active substances suchas D4F, reverse D4F, LXR modulating active substances and FXR modulatingactive substances; CETP inhibitors such as torcetrapib, JTT-705(dalcetrapib) or compound 12 from WO 2007/005572 (anacetrapib); LDLreceptor modulators; MTP inhibitors (e.g. lomitapide); and ApoB100antisense RNA.

A dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mgonce a day.

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan.

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat);dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as theCBI antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptoragonists; NPYS as well as NPY2 antagonists (e.g. velneperit); beta3-ARagonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such asAPD 356(lorcaserin); myostatin inhibitors; Acrp30 and adiponectin;steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS)inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy3-36; orexin receptor antagonists; and tesofensine; as well as the dualcombinations bupropion/naltrexone, bupropion/zonisamide,topiramate/phentermine and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

Further, the certain DPP-4 inhibitor of this invention may be used incombination with a substrate of DPP-4 (particularly with ananti-inflammatory substrate of DPP-4), which may be other than GLP-1,for the purposes according to the present invention, such substrates ofDPP-4 include, for example—without being limited to, one or more of thefollowing:

Incretins:

Glucagon-like peptide (GLP)-1

Glucose-dependent insulinotropic peptide (GIP)

Neuroactive:

Substance P

Neuropeptide Y (NPY)

Peptide YY

Energy Homeostasis:

GLP-2

Prolactin

Pituitary adenylate cyclase activating peptide (PACAP)

Other Hormones:

PACAP 27

Human chorionic gonadotrophin alpha chain

Growth hormone releasing factor (GHRF)

Luteinizing hormone alpha chain

Insulin-like growth factor (IGF-1)

CCL8/eotaxin

CCL22/macrophage-derived chemokine

CXCL9/interferon-gamma-induced monokine

Chemokines:

CXCL10/interferon-gamma-induced protein-10

CXCL11/interferon-inducible T cell a chemoattractant

CCL3L1/macrophage inflammatory protein 1alpha isoform

LD78beta

CXCL12/stromal-derived factor 1 alpha and beta

Other:

Enkephalins, gastrin-releasing peptide, vasostatin-1,

peptide histidine methionine, thyrotropin alpha

Further or in addition, the certain DPP-4 inhibitor of this inventionmay be used in combination with one or more active substances which areindicated in the treatment of nephropathy, such as selected fromdiuretics, ACE inhibitors and/or ARBs.

Further or in addition, the certain DPP-4 inhibitor of this inventionmay be used in combination with one or more active substances which areindicated in the treatment or prevention of cardiovascular diseases orevents (e.g. major cardiovascular events).

Moreover, optionally in addition, the certain DPP-4 inhibitor of thisinvention may be used in combination with one or more antiplateletagents, such as e.g. (low-dose) aspirin (acetylsalicylic acid), aselective COX-2 or nonselective COX-1/COX-2 inhibitor, or a ADP receptorinhibitor, such as a thienopyridine (e.g. clopidogrel or prasugrel),elinogrel or ticagrelor, or a thrombin receptor antagonist such asvorapaxar.

Yet moreover, optionally in addition, the certain DPP-4 inhibitor ofthis invention may be used in combination with one or more anticoagulantagents, such as e.g. heparin, a coumarin (such as warfarin orphenprocoumon), a pentasaccharide inhibitor of Factor Xa (e.g.fondaparinux), or a direct thrombin inhibitor (such as e.g. dabigatran),or a Faktor Xa inhibitor (such as e.g. rivaroxaban or apixaban oredoxaban or otamixaban).

Still yet moreover, optionally in addition, the certain DPP-4 inhibitorof this invention may be used in combination with one or more agents forthe treatment of heart failure (such as e.g. those mentioned in WO2007/128761).

The dosage of the active components in the combinations or compositionsin accordance with the present invention may be varied, although theamount of the active ingredients shall be such that a suitable dosageform is obtained. Hence, the selected dosage and the selected dosageform shall depend on the desired therapeutic effect, the route ofadministration and the duration of the treatment. Dosage ranges for thecombination may be from the maximal tolerated dose for the single agentto lower doses.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Examples

In order that this invention be more fully understood, the herein-givenexamples are set forth. Further embodiments, features or aspects of thepresent invention may become apparent from the examples. The examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

Treatment of Patients with Type 2 Diabetes Mellitus having Albuminuria:

A multicentre, double-blind, placebo-controlled clinical trialinvestigates glycaemic and renal effects of linagliptin in patients withtype 2 diabetes, albuminuria and estimated GFR ≥30 ml/min/1.73 m2 (withor without renal function impairment).

A total of 360 patients with type 2 diabetes (HbA1c 6.5-10%) andpersistent albuminuria (urinary albumin-to-creatinine ratio [UACR]30-3000 mg/gCr; i.e. micro- or macro-albuminuria) despite stablebackground (standard-of-care) of single renin-angiotensin systemblockade (ARB or ACE inhibitor) are randomised to either linagliptin 5mg (n=182) or placebo (n=178) for 24 weeks. Primary glycaemic and keysecondary renal surrogate endpoints are HbA1c and UACR change frombaseline over 24 weeks, respectively.

Overall mean (SD) baseline HbA1c and geometric mean (gMean) UACR are7.8% (0.9) and 126 mg/gCr (microalbuminuria, 73.7%; macroalbuminuria,20.3%), respectively. At week 24, the adjusted mean (SE) % change frombaseline in HbA1c for linagliptin and placebo is −0.63 (0.06) and −0.03(0.06), respectively; the placebo-adjusted mean HbA1c change frombaseline is −0.60% (95% Cl −0.78, −0.43; p<0.0001). The gMean fortime-weighted average of % change (95% Cl) from baseline in UACR over 24weeks for linagliptin and placebo is −11.0% (−16.8, −4.7) and −5.1%(−11.4, 1.6), respectively; the placebo-adjusted gMean for time-weightedaverage of % change in UCAR from baseline is −6.0% (95% Cl −15.0, 3.0;NS).

Exploratory analyses of the subgroup of patients treated withlinagliptin on a background of metformin (as well as of those withmoderate renal impairment CKD3, eGFR of 30-60 ml/min/1.73m2) in theabove study show a numerically larger difference in the changes frombaseline vs. placebo in urinary albumin to creatinine ratio (UACR)compared to patients without the combination with metformin (post hocsubgroup analysis of key secondary endpoint).

Alternatively, the renal effects can be evaluated by a scoring system(diabetic nephropathy score) for staging diabetic kidney disease such asgenerated from the profiles of a urinary biomarker panel composed ofalpha2-HS-glycoprotein, alpha-1-antitrypsin and acid-1-glycoprotein.

Treatment of Patients with Type 2 Diabetes Mellitus at HighCardiovascular and Renal Microvascular Risk:

The long term impact on cardiovascular and renal (microvascular) safety,morbidity and/or mortality and relevant efficacy parameters (e.g. HbA1c,fasting plasma glucose, treatment sustainability) of treatment withlinagliptin in combination with metformin in a relevant population ofpatients with type 2 diabetes mellitus (such as e.g. at high vascularrisk, at advanced stage of diabetic kidney disease) can be investigatedas follows:

Type 2 diabetes patient with insufficient glycemic control (naïve orpre-treated with any antidiabetic background medication includingmetformin, excluding treatment with GLP-1 receptor agonists, DPP-4inhibitors or SGLT-2 inhibitors if ≥consecutive 7 days, e.g. havingHbA1c 6.5-10%), and high risk of cardiovascular events, e.g. defined by:albuminuria (micro or macro) and previous macrovascular disease: e.g.defined according to Condition I as indicated below;

-   -   and/or    -   impaired renal function: e.g. as defined according to Condition        II as indicated below;

Condition I:

-   -   albuminuria (such as e.g. urine albumin creatinine ratio (UACR)        ≥30 mg/g creatinine or ≥30 mg/l (milligram albumin per liter of        urine) or ≥30 μg/min (microgram albumin per minute) or ≥30 mg/24        h (milligram albumin per 24 hours)) and    -   previous macrovascular disease, such as e.g. defined as one or        more of a) to f):    -   a) previous myocardial infarction (e.g. >2 months),    -   b) advanced coronary artery disease, such as e.g. defined by any        one of the following:    -   ≥50% narrowing of the luminal diameter in 2 or more major        coronary arteries (e.g. LAD (Left Anterior Descending), CX        (Circumflex) or RCA (Right Coronary Artery)) by coronary        angiography or CT angiography,    -   left main stem coronary artery with ≥50% narrowing of the        luminal diameter,    -   prior percutaneous or surgical revascularization of 2 major        coronary arteries (e.g. ≥2 months),    -   combination of prior percutaneous or surgical revascularization,        such as e.g. of 1 major coronary artery (e.g. ≥2 months) and        ≥50% narrowing of the luminal diameter by coronary angiography        or CT angiography of at least 1 additional major coronary        artery,    -   c) high-risk single-vessel coronary artery disease, such as e.g.        defined as the presence of ≥50% narrowing of the luminal        diameter of one major coronary artery (e.g. by coronary        angiography or CT angiography in patients not revascularised)        and at least one of the following:    -   a positive non invasive stress test, such as e.g. confirmed by        either:    -   a positive ECG exercise tolerance test in patients without left        bundle branch block, Wolff-Parkinson-White syndrome, left        ventricular hypertrophy with repolarization abnormality, or        paced ventricular rhythm, atrial fibrillation in case of        abnormal ST-T segments,    -   a positive stress echocardiogram showing induced regional        systolic wall motion abnormalities,    -   a positive nuclear myocardial perfusion imaging stress test        showing stress induced reversible perfusion abnormality,    -   patient discharged from hospital with a documented diagnosis of        unstable angina pectoris (e.g. ≥2-12 months),    -   d) previous ischemic or haemorrhagic stroke (e.g. >3 months),    -   e) presence of carotid artery disease (e.g. symptomatic or not),        such as e.g. documented by either:    -   imaging techniques with at least one lesion estimated to be ≥50%        narrowing of the luminal diameter,    -   prior percutaneous or surgical carotid revascularization,    -   f) presence of peripheral artery disease, such as e.g.        documented by either:    -   previous limb angioplasty, stenting or bypass surgery,    -   previous limb or foot amputation due to macrocirculatory        insufficiency,    -   angiographic evidence of peripheral artery stenosis ≥50%        narrowing of the luminal diameter in at least one limb (e.g.        definition of peripheral artery: common iliac artery, internal        iliac artery, external iliac artery, femoral artery, popliteal        artery),

Condition II:

-   -   impaired renal function (e.g. with or without CV        co-morbidities), such as e.g. defined by:    -   impaired renal function (e.g. as defined by MDRD formula) with        an estimated glomerular filtration rate (eGFR) 15-45 mL/min/1.73        m² with any urine albumin creatinine ratio (UACR), and/or    -   impaired renal function (e.g. as defined by MDRD formula) with        an with an estimated glomerular filtration rate (eGFR) ≥45-75        mL/min/1.73 m² with an urine albumin creatinine ratio        (UACR) >200 mg/g creatinine or >200 mg/l (milligram albumin per        liter of urine) or >200 μg/min (microgram albumin per minute)        or >200 mg/24 h (milligram albumin per 24 hours);    -   are treated over a lengthy period (e.g. for 4-5 years, or        preferably at least 48 months) with linagliptin (preferably 5 mg        per day, administered orally) in combination with metformin        (optionally in combination with one or more further active        substances, e.g. such as those described herein) and compared        with patients who have been treated with placebo (as add-on        therapy on top of standard of care).

Evidence of the therapeutic success compared with patients who have beentreated with placebo can be found in non-inferiority or superioritycompared to placebo, e.g. in the (longer) time taken to first occurrenceof cardio- or cerebrovascular events, e.g. time to first occurrence ofany of the following components of the composite CV endpoint:cardiovascular death (including fatal stroke, fatal myocardialinfarction and sudden death), non-fatal myocardial infarction (excludingsilent myocardial infarction), non-fatal stroke, and (optional)hospitalization e.g. for unstable angina pectoris; and/or

-   -   in the (longer) time taken to first occurrence of renal        microvascular events, e.g. time to first occurrence of any of        the following components of the composite renal endpoint: renal        death, sustained end-stage renal disease, and sustained decrease        of 50% or more in eGFR.

Further therapeutic success can be found in the (smaller) number of orin the (longer) time taken to first occurrence of any of: cardiovasculardeath, (non)-fatal myocardial infarction, silent MI, (non)-fatal stroke,hospitalization for unstable angina pectoris, hospitalization forcoronary revascularization, hospitalization for peripheralrevascularization, hospitalization for congestive heart failure, allcause mortality, renal death, sustained end-stage renal disease, loss ineGFR, new incidence of macroalbuminuria, progression in albuminuria,progression in CKD, need for anti-retinopathy therapy; or improvement inalbuminuria, renal function, CKD; or improvement in cognitive functionor prevention of/protection against accelerated cognitive decline.

Cognitive functions can be assessed by standardized tests as measure ofcognitive functioning such as e.g. by using the Mini-Mental StateExamination (MMSE), the Trail Making Test (TMT) and/or the VerbalFluency Test (VFT).

Additional therapeutic success (compared to placebo) can be found ingreater change from baseline in HbA1c and/or FPG.

Further additional therapeutic success can be found in greaterproportion of patients on study treatment at study end maintain glycemiccontrol (e.g. HbA1c</=7%).

Further additional therapeutic success can be found in greaterproportion of patients on study treatment who at study end maintainglycemic control without need for additional antidiabetic medication(during treatment) to obtain HbA1c</=7%.

Further additional therapeutic success can be found in lower proportionof patients on study treatment initiated on insulin or treated withinsulin or in lower dose of insulin dose used.

Further additional therapeutic success can be found in lower change frombaseline in body weight or greater proportion of patients with ≤2%weight gain or lower proportion of patients with ≥2% weight gain atstudy end.

Respective subgroup analysis may be made in this study for patientshaving chronic kidney disease (CKD) such as e.g. up to stage 3 and/orhaving estimated glomerular filtration rate (eGFR; mL/minute/1.73 m²)levels down to 45, or down to 30, such as for patients with (chronic)renal impairment of moderate stage (CKD stage 3, eGFR 30-60),particularly of mild-to-moderate stage (CKD stage 3a) such as havingeGFR levels 45-59 or of moderate-to-severe stage (CKD stage 3b) such ashaving eGFR levels 30-44; optionally with or without micro- ormacroalbuminuria.

1. A method of using linagliptin, or a pharmaceutically acceptable saltthereof, in combination with metformin, and optionally one or morefurther active agents selected from the group consisting of insulin anda sulfonylurea to treat a type 2 diabetes patient having estimatedglomerular filtration rate (eGFR; mL/minute/1.73 m²) levels down to 45or down to
 30. 2. The method of claim 1, wherein the type 2 diabetespatient has an estimated glomerular filtration rate (eGFR;mL/minute/1.73m²) level down to
 45. 3. The method of claim 1, whereinthe type 2 diabetes patient has an estimated glomerular filtration rate(eGFR; mL/minute/1.73 m²) level down to
 30. 4. The method of claim 2,wherein linagliptin and metformin are administered in a singlepharmaceutical composition, such as e.g. in form of a single oral dosageform (e.g. tablet).
 5. The method of claim 4, wherein the linagliptin ispresent in the composition in a dosage strength of 2.5 mg; or of 5 mg.6. The method of claim 5, wherein the metformin is present in thecomposition in a dosage strength of 500 mg, 850 mg or 1000 mg in form ofimmediate release metformin; or 500 mg, 750 mg, 1000 mg, 1500 mg or 2000mg in form of extended release metformin.
 7. The method of claim 4,wherein the pharmaceutical composition comprises 2.5 mg linagliptin and500 mg, 850 mg or 1000 mg metformin in immediate release form, andoptionally one or more pharmaceutically auxiliaries
 8. The method ofclaim 4, wherein the pharmaceutical composition comprises 5 mglinagliptin and 1000 mg metformin in extended release form, andoptionally one or more pharmaceutically auxiliaries, or wherein thepharmaceutical composition comprises 2.5 mg linagliptin and 750 mg or1000 mg metformin in extended release form, and optionally one or morepharmaceutically auxiliaries.
 9. The method of claim 1, whereinlinagliptin is administered in a total oral daily dose of 5 mg.
 10. Themethod of claim 2, wherein linagliptin is administered in a total oraldaily dose of 5 mg, wherein the 5 mg daily dose is administered as 2.5mg linagliptin twice daily or 5 mg linagliptin once daily.
 11. A methodof using linagliptin, or a pharmaceutically acceptable salt thereof, incombination with metformin, to treat a type 2 diabetes patient havingeGFR level 30-44, wherein the maximum daily dose of metforminhydrochloride is 1000 mg, wherein linagliptin and metformin areadministered in a single oral dosage form comprising 2.5 mg linagliptinand 500 mg metformin, and optionally one or more pharmaceuticallyauxiliaries, and wherein the single oral dosage form is administeredorally twice daily to the patient.